Photoselective vaporization with green laser versus monopolar transurethral resection for benign prostatic hyperplasia

The objective was to evaluate the efficacy and safety of photoselec-tive vaporization of the prostate with green light laser (PVP-GL) compared to monopolar transurethral resection (TURP-M) in reducing lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH) in a systematic review and meta-analysis of randomized clinical trials (RCTs). The data sources were Medline, CENTRAL/Cochrane, LILACS


INTRODUCTION
Surgical treatment is one of the cornerstones in managing lower urinary tract symptoms secondary to benign prostatic obstruction.It aims to remove the prostate adenoma through resection, enucleation, or evaporation 1,2 .Transurethral resection of the prostate (TURP), in both monopolar (TURP-M) and bipolar (TURP-B) forms, remains a widely investigated alternative 3 .Due to its widespread availability and effectiveness, TURP-M (the method of choice since the 1970s) is considered the reference technique for the surgical treatment of lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) in men with prostates between 30 and 80 mL.The technique removes tissue from the transition zone of the gland in varying degrees, resulting in a reduction in prostate volume and prostate-specific antigen by 25-58% 1,4 .TURP has demonstrated a high success rate and low reintervention rate in long-term follow-up 5 .However, increasing evidence indicates that this invasive procedure is also associated with serious complications such as bleeding, urethral strictures, urinary incontinence, and transurethral resection syndrome (TURS) [6][7][8] .
In recent years, various techniques have been developed as safe and effective alternatives to TURP-M.One of these is photoselective vaporization of the prostate with PVP-GL.This technique is generally performed with a green laser with a wavelength

Eligibility criteria
The eligibility criteria define the specific elements to address the clinical question outlined in the objectives of this evaluation, the requirements of greater consistency and scientific strength for study inclusion, and the main reasons for the exclusion of the retrieved evidence.

Inclusion criteria for studies
• Patients: with lower urinary tract symptoms secondary to benign prostatic hyperplasia, with surgical indication.
• Intervention: selective photovaporization of the prostate with a green light laser.• Comparison: monopolar transurethral resection of the prostate.• Outcomes: relevant clinical outcomes of efficacy and safety.• Study design: double-blind, parallel-controlled RCTs.
• Full text available.
Excluded studies: Crossover RCTs; systematic reviews with or without meta-analysis; narrative reviews; observational studies and/or case series; studies with surrogate endpoints; and the absence of extractable data regarding outcomes (absolute numbers and/or means) or the absence of another study measuring the same outcome, thereby preventing aggregation of their results in the meta-analysis.

Evidence search
Searches were conducted in the following databases of published scientific information: Medline/PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), LILACS, and ClinicalTrials.gov(CT.gov) for unpublished registry studies.Additional manual searches were performed in the reference lists of included studies and other relevant sources.The search in these databases was conducted till February 2024.
The search strategies used in each database were as follows:

Study selection and data extraction process
The evidence retrieved from the consulted databases is initially selected based on the title and abstract to meet the eligibility criteria.The studies identified in this initial selection then have Silvinato A et al.
their full texts accessed to confirm their eligibility.The retrieval process and the evaluation of the obtained titles and abstracts were conducted independently and in a blinded manner by two researchers skilled in systematic reviews (AS and IF), following the inclusion and exclusion criteria.Subsequently, the selected articles were critically evaluated for inclusion in the review.When there was a disagreement about the study selection between the researchers, a third reviewer (WMB) was consulted.
From the eligible studies, the following data will be extracted: the name of the first author and year of publication, the studied population, intervention and comparison methods, and follow-up time.Regarding the extracted data for relevant outcomes, these may include an absolute number of events or means and/or medians with their respective standard deviations or 95% confidence intervals, depending on the type of outcome.

Risk of bias and quality of evidence
Two independent reviewers assessed the risk of bias in the included studies using the items from the Cochrane Risk of Bias Tool for Randomized Trials (RoB 2) 13 , supplemented by other essential elements, and expressed as high, moderate, and low.Each domain was classified as having no bias, insufficient information, or presence of bias.Publication bias was evaluated through inspection of the funnel plot and by conducting Egger's test 14 .
The Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) 15 criteria were used as the method to assess the certainty of the effect estimate in the pooled evidence, categorizing the quality of evidence into four levels: high, moderate, low, and very low.Two reviewers evaluated the risk of bias, inconsistency, indirect evidence, imprecision, and publication bias for all reported outcomes.The quality of evidence was assessed using the Guideline Development Tool (GRADEpro GDT) 16 application and presented in GRADE evidence profiles and summary of findings tables, using standardized terminology.

Method of analysis and synthesis of results
Data will be analyzed according to the intention-to-treat principle, and the most recent follow-up data available will be included in each trial.The results for categorical outcomes will be expressed using the risk difference (RD) between intervention and control groups, using the Mantel-Haenszel method.If the RD between groups is statistically significant, it will be accompanied by a 95% confidence interval (CI) and the number needed to treat (NNT) or the number needed to harm (NNH).For continuous outcomes, the results will be the mean difference (MD) or standardized mean difference (SMD) if different scales were reported, with a 95%CI.
If there are multiple studies included with common outcomes, they will be pooled using meta-analysis, employing the Review Manager 5.4 (The Nordic Cochrane Centre, The Cochrane Collaboration) 17 .The overall risk difference or mean difference, with 95%CIs, will be the final measure used to support the synthesis of evidence that addresses the clinical question (Objective).For studies that reported data as medians and interquartile ranges, the statistical formula proposed by Hozo et al. 18 was used to estimate means and standard deviations, in accordance with the methodological guidelines of the Cochrane Handbook for Systematic Reviews 19 .For studies that did not report standard deviation (SD), it will be calculated based on sample size and standard error (SE) or 95%CI.
The estimation of the combined effect size will be conducted using a fixed-effect or random-effects model after assessing the heterogeneity results.Based on statistical heterogeneity findings, the inconsistency was assessed using the I 2 metric, which measures the percentage of variation attributable to the difference among studies rather than random variation 20 .Heterogeneity values greater than 50% were considered high.A sensitivity analysis was performed to assess the reliability of the findings of this study.A funnel plot was used to analyze asymmetry, which was evaluated after excluding outliers.

Evidence synthesis and conclusion
The evidence synthesis will present the results directly from the analyses, considering the benefits, harm, and lack of difference between the use of PVP-GL compared to TURP-M.The conclusions will primarily consider evidence of at least moderate quality, assessing the presence of beneficial or harmful effects.Additionally, it will consider the favorable balance between benefit and harm in patients with lower urinary tract symptoms caused by benign prostatic hyperplasia and surgical indications.

RESULTS
In seeking evidence, 1,102 articles were retrieved from the Medline, CENTRAL, LILACS, and CT.gov databases.Manual and/or gray literature searches did not identify any additional works.After removing duplicates and selecting based on title and/or abstract, 39 articles met the previously established eligibility criteria (Methodology).The full texts of these 39 articles were accessed for analysis.

Green laser vsrsus monopolar resection for benign prostatic hyperplasia
The reasons for excluding the other 26 studies are detailed in Figure 1 and in the References section, under the heading "References of Excluded Studies and Their Reasons." Figure 1 presents a flow diagram illustrating the sequence from the retrieval to the selection of evidence for this assessment.The main baseline characteristics and details of each included trial are reported in Table 1 (Appendices).

Risk of bias in the studies
Of the 13 RCTs included [21][22][23][24][25][26][27][28][29][30][31][32][33] , only one study reported blinding of the assessors but did not perform a sample size calculation 27 (with 10 patients); four studies did not conduct an intention-totreat (ITT) 21,22,24,28 , and a total of five studies did not perform a sample size calculation 22,24,26,27,33 .The risk of bias assessment for each individual study, using the RoB 2 tool 13 and additional key elements, is reported in Table 2 (Appendices).The nature of the intervention prevented the blinding of the surgeons.The study was considered double-blinded if patients and outcome assessors were blinded.Any disagreements were resolved by consensus.
The Egger's test (funnel plot) did not identify any outlier studies that would justify the observed heterogeneity (publication bias) (Figure 3 in Appendices).The 70% heterogeneity (I 2 ) was not altered with sensitivity analysis due to the absence of outlier studies and/or publication bias.

Functional outcomes
Initial data, including IPSS, Qmax, and PVR for all participants in the PVP-GL and TURP-M groups, were similar (Table 1 in Appendices).
Prostate symptoms: In a subgroup analysis by follow-up time (6, 12, 24, and 36 months), prostate symptoms were evaluated using the IPSS, with a total score ranging from 0 to 35, classifying patients from asymptomatic to very symptomatic.At 6 months, compared to TURP-M, PVP-GL showed a less favorable effect, resulting in an average increase of 0.85 points in the IPSS score (MD=0.85[95%CI, 0.04-1.65];p=0.04;I 2 =87%) (Figure 6).The certainty of evidence for this difference was classified as low (Table 4 in Appendices).
At 12, 24, and 36 months, there was no difference in the IPSS between the two procedures (p>0.05 for all comparisons) (Figure 6).The certainty of evidence for this lack of difference is very low (Table 4 in Appendices).
The Egger's test did not identify any outlier studies that would justify the observed heterogeneity (Figure 3 in Appendices).High heterogeneity was observed across all follow-up periods (87-94%), but this was not altered by sensitivity analysis due to the absence of outlier studies and/or publication bias.
Maximum urinary flow rate (Qmax, mL/s): In 1998, the International Continence Society (ICS) defined Qmax values above 15 mL/s as normal, values between 10 and 15 mL/s as inconsistent, and values below 10 mL/s as pathological 34 .
A subgroup analysis by follow-up time (6, 12, 24, and 36 months) evaluated Qmax.At no time points during follow-up,  there was a difference in Qmax between the two procedures (p>0.05 for all comparisons) (Figure 7).The certainty of evidence for this lack of difference ranged from low to very low (Table 4 in Appendices).The Egger's test did not identify any outlier studies that would justify the observed heterogeneity (Figure 3 in Appendices).There was high heterogeneity in the 6-, 24-, and 36-month follow-ups (72-91%), but this heterogeneity was not altered by sensitivity analysis due to the absence of outlier studies and/or publication bias.
The evidence certainty ranged from low to very low (Table 4 in Appendices).
At 24 months, PVP-GL has a less favorable outcome, increasing the PVR by 1.52 mL (MD=1.52 [95%CI, 0.89-2.5 mL]; p=0.00001;I 2 =0%) (Figure 8).The evidence certainty was moderate (Table 4 in Appendices).The Egger's test identified studies with divergent results that justified the observed heterogeneity at 6 and 36 months (Figure 3 in Appendices).To evaluate the influence of these studies, a sensitivity analysis was performed.
At 6 months, the study by Horasanli et al. was removed due to a much larger effect compared to other studies.This adjustment decreased heterogeneity (I 2 =24%) but did not change the significance of the difference in PVR between the procedures.
At 36 months, the study by Purkait et al. was removed due to a result contradicting the other studies.This adjustment eliminated the heterogeneity (I 2 =0%) and increased the MD to 1.58 mL (95%CI, 0.89-2.26mL; p<0.00001).This result, like the 24-month observation, was unfavorable to PVP-GL.
Egger's test (funnel plot) identified one study 31 with discrepant results that accounted for the observed heterogeneity (publication bias) regarding the outcomes of blood transfusion and capsule perforation.Figure 3 (G) in Appendices presents these results.To assess the influence of this study, a sensitivity analysis was conducted.
For the outcome of blood transfusion, the study by Al-Ansai et al. was removed due to its significantly larger effect compared to the others.This adjustment reduced heterogeneity (I 2 from 68 to 41%) and the risk difference by 1%.The significance of the difference between the procedures remained (DR=5% [95%CI, 0.025-0.07];p<0.0001;NNT=22 [95%CI, 15-40]), with a still favorable benefit to PVP-GL.
For the outcome of capsule perforation, the study by Al-Ansari et al. was also removed for the same reason as in the blood transfusion outcome.Heterogeneity was reduced from 71 to 0% and the risk difference by 4%.The significance of the difference between the procedures remained (DR=4.4% [95%CI, 0.08-0.10];p=0.03;NNT=23 [95%CI, 13-104]), as well as the favorable benefit to PVP-GL.

EVIDENCE SYNTHESIS
The PVP-GL compared to TURP-M

IPSS
• At 6 months, it shows a less favorable effect, as it increases the IPSS score by an average of 0.85 points (95%CI, 0.04-1.65).The certainty of evidence for this difference was classified as low.• At 12, 24, and 36 months, there is no difference in IPSS (p>0.05 for these comparisons).The certainty of evidence is very low for this lack of difference.

Qmax (mL/s)
• There is no difference in Qmax at the 6-, 12-, 24-, and 36-month follow-ups (p>0.05 for these comparisons).The certainty of evidence for this lack of difference varies from low to very low.

PVR (mL)
• It does not show a difference at 6, 12, and 36 months (p>0.05 for these comparisons).The certainty of evidence for this lack of difference varies from low to very low.• At 24 months, it shows a less favorable result, as it increases the PVR by 1.52 mL (95%CI, 0.89-2.5).This response does not persist at 36 months, as seen above.The certainty of evidence for this difference is moderate.
Green laser vsrsus monopolar resection for benign prostatic hyperplasia

DISCUSSION
Green light laser photoselective vaporization (PVP-GL) has emerged as a promising technique in the management of benign prostatic hyperplasia, showing favorable results when compared to monopolar transurethral resection of the prostate (TURP-M) [35][36][37] .Our meta-analysis addressed a variety of perioperative outcomes, functional outcomes, and complications.We provided a comprehensive view of the effectiveness and safety of this technique, including only RCTs using green light lasers (KTP, 532 nm wavelength) for PVP.A separate analysis of the use of 80-W and 120-W lasers was challenging due to the scarcity of available data.Therefore, despite well-known limitations and subsequent improvements in the laser, these were considered similar interventions for the purposes of this meta-analysis.
Regarding perioperative outcomes, we observed that PVP-GL increases the average procedure time by 8 min.Although this increase is statistically significant (MD=7.74min [95%CI, 4.53-10.96min]; p<0.00001), it is important to note that the difference is moderate and may not be clinically relevant.Additionally, the average reduction of 2 days in hospitalization time and 1 day in catheterization time, although statistically significant, are based on low-certainty evidence, which requires caution in interpreting these results.
PVP-GL showed mixed results compared to TURP-M for functional outcomes.We observed that PVP-GL showed an average increase in IPSS score at 6 months (MD=0.85[95%CI, 0.04-1.65];p=0.04), but this difference did not persist in subsequent follow-ups at 12, 24, and 36 months.The lack of significant difference in IPSS in the long term suggests that PVP-GL maintains comparable results to TURP-M over time.
Similarly, there were no significant differences in Qmax and PVR at different follow-ups, highlighting the equivalence of these techniques in terms of functional performance.Sensitivity analysis for IPSS and Qmax outcomes did not identify outlier studies and/or publication bias, maintaining high heterogeneity at follow-up periods.However, for RVR outcome, discrepant studies were identified at 6 and 36 months.Removing these studies resulted in changes in heterogeneity, but not with the same significance as the result at 6 months; at 36 months, the elimination of heterogeneity was accompanied by a less favorable result for PVP-GL (increased MD to 1.58 mL [95%CI, 0.89-2.26mL; p<0.00001]), although it is a small difference and may not be clinically relevant.
In summary, our analysis suggests that PVP-GL offers advantages in terms of recovery time and perioperative complications, with comparable functional outcomes to TURP-M in the long term.However, it is important to recognize the limitations of the available evidence, especially regarding perioperative and functional outcomes.For these events, the certainty of evidence is low or very low due to a high risk of bias in the included studies, high heterogeneity, and very wide confidence intervals for many of the outcomes.Despite these limitations, this study provides the most up-to-date information on the comparison of PVP-GL and TURP-M in the surgical treatment of BPH.Future studies with robust designs are needed to confirm and expand these findings, providing a more solid basis, especially in relation to the certainty of evidence, and offering more precise guidelines for clinical practice.

CONCLUSION
In our meta-analysis of functional outcomes up to 3 years of follow-up after PVP-GL and TURP-M, we found that both procedures showed similar results.Although PVP-GL offers advantages in terms of recovery time and perioperative complications, it is important to highlight the potential risk of reoperation for recurrent adenoma in the long term.However, it is crucial to note that the certainty of evidence available, especially regarding perioperative and functional outcomes, is low or very low.

Figure 4 .
Figure 4. Forest plot of the comparison: 1 Green light laser photoselective vaporization versus monopolar transurethral of the prostate; outcome: 1.2 Hospitalization time (days).

Figure 5 .
Figure 5. Forest plot of the comparison: 1 Green light laser photoselective vaporization versus monopolar transurethral of the prostate; outcome: 1.3 Catheterization time (days).

Figure 6 .
Figure 6.Forest plot of the comparison: 1 Green light laser photoselective vaporization versus monopolar transurethral of the prostate; outcome: 1.4 International Prostate Symptom Score.

Figure 9 .
Figure 9. Forest plot of the comparison: 1 Green light laser photoselective vaporization versus monopolar transurethral resection of the prostate; outcome: 1.7 Complications.

Table 2 .
Risk of bias in studies.
Continuous variables were expressed as (mean±SD).PVP-GL, photoselective vaporization of the prostate with green-light laser; RTUP-M, monopolar transurethral resection of the prostate; IPSS, International Prostate Symptom Score; Qmax, maximum flow rate; PVR, post-void residual volume.APPENDICES